Age-related macular degeneration (AMD) is a late-onset, progressive, neurodegenerative disease with devastating impact on the elderly. This disease occurs primarily in people over the age of 65 years and accounts for approximately 50% of registered blindness in Western Europe and North America. AMD develops as either "dry" (atrophic) or "wet" (exudative). The pathogenesis of AMD is clearly multifactorial with genetic and environmental factors including aging, smoking, diet, gender, oxidative stress, and inflammation playing roles in onset and progression. We have recently developed a murine model of AMD by combining three of the risk factors for AMD: advanced age, apolipoprotein E [apoE (protein); human APOE (gene)] isoform expression and exposure to a high- fat, high-cholesterol (HF-C) diet. These mice develop pathological changes similar to the morphologic hallmarks observed in dry and wet human AMD, including thick diffuse sub-retinal pigment epithelium (RPE) deposits, lipid- rich drusen-like deposits, thickening of Bruch's membrane, patchy regions of RPE atrophy overlying photoreceptor degeneration and choroidal neovascularization (CNV). Importantly, these changes require the presence of all three risk factors. This animal model of spontaneously-occurring CNV is the first to incorporate physiologically-relevant risk factors of human disease. In this proposal, we aim to develop and establish this animal model of AMD, beyond its currently documented history, to document the reproducibility of the phenotype; to correlate changes in the RPE, Bruch's membrane and choroid to degenerative effects in the photoreceptors and to identify molecular pathways responsible for these changes. We expect that elucidation of the pathogenesis of the changes that occur in this model will contribute to our understanding of unknown molecular mechanisms leading to the neuropathology of AMD. To this end, we propose three Specific Aims: (1) Determine whether prolonged exposure to a HF-C diet increases severity of spontaneous CNV and sub-RPE deposit formation in a mouse model of AMD; (2) Examine and evaluate degenerative and synaptic changes in the retina in APOE mice with a focus on photoreceptors; (3) to identify genes in the RPE, choroid and retina that regulate pathways responsible for the development of deposits and CNV in the eyes of these apoE mice, using comparative microarray expression profiling. Analysis of these animals will provide insight into the pathogenesis of AMD as well as a means to separate the relative contribution and degenerative effects of specific risk factors. [unreadable] [unreadable] [unreadable]